Soft tissue sarcoma (STS) is one of the difficult diseases both for diagnosis and treatment. STSs are generally classified according to their histological resemblance to mature, normal tissues (Weiss, S. W. and Goldblum, J. R., Enzinger and Weiss's Soft Tissue Tumors, 4th edition. St. Louis: Mosby, 2001). However, some sarcomas such as synovial sarcoma (SS) have no histological counterparts in normal tissues, and therefore are grouped together as “miscellaneous soft tissue tumors” (Weiss, S. W. and Sobin, L., Histological typing of soft tissue tumours, In: World Health Organization International Histological Classification of Tumours, 2nd edition. Berlin: Springer-Verlag, 1994). Synovial sarcoma predominantly affects the lower extremities of adolescents and young adults at 15-40 years of age (Weiss, 2001 supra). The clinicopathological designation was originally given because SS occurs primarily in the vicinity of large joints and histologically resembles developing synovium (Smith, L. W., Synoviomata. Am. J. Pathol., 3: 355, 1927). However, subsequent immunohistochemical and ultrastructural studies (Ghadially, F. N., Ultrastruct. Pathol., 11: 147-51, 1987; Smith, M. E. et al., Histopathology, 26: 279-81, 1995) have revealed significant differences between the tumor cells of SS and synovial cells. In addition, SS can arise where synovial structures are rare or absent, including the lung (Roberts, C. A. et al., Cancer Genet. Cytogenet., 88: 49-52, 1996), heart (Iyengar, V. et al., Arch. Pathol. Lab. Med., 119: 1080-2, 1995), kidney (Argani, P. et al., Am. J. Surg. Pathol., 24: 1087-96, 2000), digestive tract (Billings, S. D. et al., Mod. Pathol., 13: 68-76, 2000), and bone marrow (Hiraga, H. et al., J. Bone Joint Surg. Am., 81: 558-63, 1999). Those data support the hypothesis that SS may originate from cells that are widely distributed in a variety of tissues.
Among several histological findings the most distinctive feature of SS is epithelial differentiation. Based on the presence or absence of an epithelial component, SS is classified into two major subtypes: biphasic, composed of distinct epithelial and spindle tumor cells, and monophasic, occupied by a fibrosarcoma-like spindle tumor cells and no detectable epithelial components (Weiss, 2001 supra). However, as the proportion and features of the epithelial component vary significantly among biphasic tumors, transition from one to the other subtype may be gradual rather than abrupt.
Although the histogenesis of SS remains unclear, molecular analysis of mechanisms underlying tumorigenesis of SS did progress notably with the discovery that a SYT-SSX fusion gene is an SS-specific genetic alteration (Clark, J. et al., Nat. Genet., 7: 502-8, 1994; Skytting, B. et al., J. Natl. Cancer Inst., 91: 974-5, 1999).
On the other hand, molecular target therapy using humanized monoclonal antibodies such as trastuzumab (Herceptin) against ErbB2 (Fendly, B. M. et al., Cancer Res. 50: 1550-8., 1990) and rituximab (Rituxan) against CD20 (Maloney, D. G. et al., Blood. 90: 2188-95., 1997) has recently contributed to the improvement of treatment outcomes in some cases of breast cancer and malignant lymphoma. These promising therapies are the first examples of genomic research-based cancer drugs that bind directly to targeted proteins on the surface of tumor cells. The humanized antibodies are thought to exert an antitumor effect through inhibition of growth signal transduction by the blocking of the cell-surface receptor, and down-regulation of target molecules by interaction with specific antibodies and/or antibody-dependent cell-mediated cytotoxicity (ADCC). Although the precise mechanisms of the antibody-based antitumor effect remain to be elucidated, these therapies are promising alternatives, especially in the treatment of chemoresistant or radioresistant cancers.
Among sarcomas defined as malignant tumors occurring in the mesenchymal tissues, osteosarcomas, Ewing's sarcoma and rhabdmyosarcomas are generally sensitive to chemotherapy. Many other sarcomas, however, especially spindle cell sarcomas in adults, are difficult diseases to treat due to chemo- and radioresistance (Crist, W. M. et al, J Clin Oncol. 19: 3091-102., 2001; Wunder, J. S. et al., J Bone Joint Surg Am. 80: 1020-33., 1998; Ferguson, W. S. and Goorin, A. M., Cancer Invest. 19: 292-315., 2001; Adjuvant chemotherapy for localised resectable soft-tissue sarcoma of adults: meta-analysis of individual data. Sarcoma Meta-analysis Collaboration, Lancet. 350: 1647-54., 1997). SS is a prototype of such tumors, and novel treatment modalities including antibody-based therapy should be developed for further improvement of outcomes, although the prognosis of SS has improved with advances in multidisciplinary treatment.
For the development of antibody-based therapy against target tumors, a critical key is identification of a cell-surface molecule that is overexpressed in the majority of the target tumors and whose expression is absent or minimal in the normal organ tissues. However, it is difficult to identify proteins specifically expressed in tumors, and there have been no reports of such proteins specifically expressed in synovial sarcoma and other tumors against which antibody-based therapies are desired to be established.